eMedicine Specialties > Pediatrics: Cardiac Disease and Critical Care Medicine > Neonatology

Hypoxic-Ischemic Encephalopathy: Differential Diagnoses & Workup

Author: Santina A Zanelli, MD, Assistant Professor, Department of Pediatrics, Division of Neonatology, University of Virginia Health System
Coauthor(s): Dirk P Stanley, MD, Resident Physician, Department of Pathology, University of Virginia Health System; David Kaufman, MD, ECMO Director, Associate Professor of Pediatrics, Department of Pediatrics, Division of Neonatology, University of Virginia Health System
Contributor Information and Disclosures

Updated: Dec 15, 2008

Differential Diagnoses

Methylmalonic Acidemia
Propionic Acidemia (Propionyl CoA Carboxylase Deficiency)

Other Problems to Be Considered

Other inborn errors of metabolism including nonketotic hyperglycinemia, disorders of pyruvate metabolism, and urea cycle defects
Mitochondrial disorders
Neuromuscular disorders including neonatal myopathies
Brain tumors
Developmental defects
Infections

Workup

Laboratory Studies

No specific test can always confirm or exclude a diagnosis of hypoxic-ischemic encephalopathy (HIE) because the diagnosis is made based on the history and physical and neurological examinations. Many of the tests are performed to assess the severity of brain injury and to monitor the functional status of systemic organs. As always, the results of the tests should be interpreted in conjunction with the clinical history and the findings from physical examination.

Laboratory studies should include the following:

• Serum electrolytes
  • In severe cases, daily assessment of serum electrolytes are valuable until the infant's status improves. Markedly low serum sodium, potassium, and chloride levels in the presence of reduced urine flow and excessive weight gain may indicate acute tubular damage or inappropriate antidiuretic hormone (IADH), particularly during the initial 2-3 days of life.
  • Similar changes may be seen during recovery; increased urine flow may indicate ongoing tubular damage and excessive sodium loss relative to water loss
• Renal function studies: Serum creatinine levels, creatinine clearance, and BUN levels suffice in most cases.
• Cardiac and liver enzymes: These values are an adjunct to assess the degree of hypoxic-ischemic injury to these other organs. These findings may also provide some insight into injuries to other organs, such as the bowel.
• Coagulation system evaluation: This includes prothrombin time, partial thromboplastin time, and fibrinogen levels.
• ABG: Blood gas monitoring is used to assess acid-base status and to avoid hyperoxia and hypoxia as well as hypercapnia and hypocapnia.

Imaging Studies

• Brain MRI
  • MRI is the imaging modality of choice for the diagnosis and follow-up of infants diagnosed with moderate-to-severe hypoxic-ischemic encephalopathy. Conventional MRI provides information on the status of myelination and preexisting developmental defects of the brain. When performed after the first day (and particularly after day 4), it also accurately reveals patterns of injury, including the following:
    • Loss of cerebral gray and white matter differentiation
    • Cortical highlighting (particularly in the parasagittal perirolandic cortex)
    • Basal ganglia or thalamus injury
    • Parasagittal cerebral injury
    • Decreased signal in the posterior limb of the internal capsule (PLIC)
  • Diffusion-weighted MRI scans allow earlier identification of injury patterns in the first 24-48 hours. The MRI sequence identifies areas of edema and, hence, injured areas. 
  • MRI is also a useful tool in the determination of prognosis. Studies indicate that infants with predominant injuries to the basal ganglia or thalamus have an unfavorable neurological outcome when compared with infants with a white matter predominant pattern of injury. Abnormal signals in the PLIC have also been associated with poor neurological outcome.
  • MRI is also useful for follow-up. In any newly diagnosed case of cerebral palsy, MRI should be considered because it may help in establishing the cause. Note that the interpretation of MRI in infants requires considerable expertise. 
  • Magnetic resonance spectroscopy (MRS) allows for quantification of intracellular molecules. Proton MRS allows identification of cerebral lactate, which persist for weeks following a significant hypoxic-ischemic injury.  Phosphorous MRS allows for real-time quantification of ATP, phosphorus creatinine, inorganic phosphorous, and intracellular pH levels.
• Cranial ultrasonography: Although ultrasonography is portable and convenient, the findings in hypoxic-ischemic encephalopathy may be imprecise. It can reveal intracerebral or intraventricular hemorrhage. However, visualization of posterior fossa may be difficult with routine ultrasonography. Cerebral edema may be evident in the form of decreased ventricular size or indistinct sulci and gyral patterns.
• Head CT scanning
  • A CT scan of the head can be useful to confirm cerebral edema (obliteration of cerebral ventricles, blurring of sulci), manifested as narrowness of the lateral ventricles and flattening of gyri. Areas of reduced density that indicate evolving zones of infarction may be present.
  • Evidence of hemorrhage in the ventricles or in the cerebral parenchyma may also be seen. Although intraventricular hemorrhages are rare in term infants, cerebral artery occlusions and infarctions can be detected with Doppler flow studies and confirmed with radiographic imaging using radio-opaque contrast materials. In cases of suspected posterior cranial fossa hemorrhage, a CT scan may be diagnostic.
  • An early diagnosis may help in obtaining early neurosurgical consultation and, possibly, surgical therapy. However, evidence suggests that even a single CT scan exposes children to potentially harmful radiation. In view of this evidence, MRI has now largely supplanted head CT in the evaluation of neonates with hypoxic-ischemic encephalopathy.
• Echocardiography: In infants requiring inotropic support, echocardiography (ECHO) helps to define myocardial contractility and the existence of structural heart defects, if any.

Other Tests

• Amplitude-integrated electroencephalography (aEEG)
  • Several studies have shown that a single-channel aEEG performed within a few hours of birth can help evaluate the severity of brain injury in the infant with hypoxic-ischemic encephalopathy. The abnormalities seen in infants with moderate-to-severe hypoxic-ischemic encephalopathy include the following:
    • Discontinuous tracing characterized by a lower margin below 5 mV and an upper margin above 10 mV
    • Burst suppression pattern characterized by a background with minimum amplitude (0-2 mV) without variability and occasional high voltage bursts (>25 mV)
    • Continuous low voltage pattern characterized by a continuous low voltage background (<5 mV)
    • Inactive pattern with no detectable cortical activity
    • Seizures, usually seen as an abrupt rise in both the lower and upper margins
  • In addition, aEEG findings have been used as criteria for inclusion in the CoolCap trial of selective head cooling.^6,7,3  However, some evidence argues against the use of aEEG as a tool to exclude infants with hypoxic-ischemic encephalopathy from receiving hypothermia therapy.
  • Although normal aEEG findings may not necessarily mean that the brain is healthy, a severe or moderately severe aEEG abnormality may indicate brain injury and poor outcome. However, a rapid recovery (within 24 h) of abnormal aEEG findings is associated with favorable outcome in 60% of cases. Finally, in a meta-analysis of 8 studies, Spitzmiller et al concluded that aEEG can accurately predict poor outcome with a sensitivity of 91% (95% CI, 87-95) and a negative likelihood ratio of 0.09 (95% CI, 0.06-0.15).⁸
  • Note that considerable training is required for conducting and properly interpreting the aEEG findings. 
• Standard EEG
  • Traditional, multichannel EEG is an integral part of the evaluation of infants diagnosed with HIE. It is a valuable tool to assess the severity of the injury and evaluate for subclinical seizures. This is particularly important for infants on assisted ventilation requiring sedation or paralysis.
  • Generalized depression of the background rhythm and voltage, with varying degrees of superimposed seizures, are early findings. Burst suppression and isoelectric EEG patterns are particularly ominous. Caution in interpreting early severe background abnormalities needs to be applied because reverting to normal background pattern in the first week of life is associated with normal outcomes. Note that large doses of anticonvulsant therapy may alter the EEG findings.
  • Serial EEGs should be obtained to assess seizure control and evolution of background abnormalities. Repeat EEGs obtained just prior to discharge can be helpful in establishing prognosis. Improvement in the EEG findings over the first week, in conjunction with improvement in the clinical condition, may help predict a better long-term outcome.
• Special sensory evaluation: Screening for hearing is now mandatory in many states in the United States; in infants with hypoxic-ischemic encephalopathy, a full-scale hearing test is preferable because of an increased incidence of deafness among infants with hypoxic-ischemic encephalopathy that require assisted ventilation.
• Retinal and ophthalmic examination: This examination may be valuable, particularly as part of an evaluation for developmental abnormalities of the brain.

Histologic Findings

The impressive array of neuropathologic findings that can result from a hypoxic-ischemic event can be primarily explained by the gestational time frame in which the event occurs. Prior to 20 weeks' gestation, fetal macrophages are capable of removing necrotic debris via phagocytosis, resulting in a smooth cavity without a gliotic response. Examples of lesions that can result from hypoxic-ischemic events in the second trimester include hydranencephaly, porencephaly, and schizencephaly. 

After 20 weeks' gestation, hypoxic-ischemic insults result in astrocyte activation with subsequent gliosis. Subependymal germinal matrix hemorrhage is most common in premature infants, with hemorrhage involving the germinal matrix, lateral ventricles, and/or the adjacent parenchyma. In the full-term infant, hypoxic-ischemic events primarily result in lesions of the cerebral cortex, basal ganglia, thalamus, brain stem, or cerebellum. The location and severity of the lesions correlate with clinical symptoms, such as disturbances of consciousness, seizures, hypotonia, oculomotor-vestibular abnormalities, and feeding difficulties. The major neuropathological patterns of injury in hypoxic-ischemic encephalopathy are listed below. More than one pattern can be present.

Selective neuronal necrosis

Selective neuronal necrosis is the most common pattern of injury observed in hypoxic-ischemic encephalopathy and is characterized by neuronal necrosis selective to areas with higher energy demands. The following 5 major patterns have been described:

• Diffuse: Sites of predilection for diffuse neuronal necrosis include the cerebral cortex (particularly the hippocampus), deep nuclear structures (thalamus, basal ganglia), brain stem, cerebellum, and anterior horn of the spinal cord.
• Cerebral cortex (deep nuclear): A predominant cerebral cortex (deep nuclear) pattern of injury is present in 35-85% of infants with hypoxic-ischemic encephalopathy. 
• Brain stem (deep nuclear): Brain stem (deep nuclear) is the predominant lesion in 15-20% of infants with hypoxic-ischemic encephalopathy. Some of these lesions can evolve to status marmoratus . The 3 major features of status marmoratus include neuronal loss, gliosis and hypermyelination. This hypermyelination is believed to be secondary to myelin sheath formation and deposition around the prominent processes of reactive astrocytes. Patchy, white discoloration of the gray matter ("marbling") is sometimes observed on gross examination. This marbling is the macroscopic correlate of the hypermyelination and glial scarring seen on histologic examination. It is not seen in its complete form until the end of the first year of life.
• Pontosubicular: This is the least common pattern and can occur in infants aged 1-2 months or younger.
• Cerebellar: This primarily occurs in premature infants.

An example of severe acute hypoxic-ischemic neuronal change with associated gliosis is shown in Media files 4-5.

Parasagittal cerebral injury

This pattern of injury is typically bilateral and involves the parasagittal areas of the cerebral cortex (see Media file 6). The regions of the cortex most susceptible to this type of injury are the end-artery zones between the anterior, middle, and posterior cerebral arteries. These so-called watershed regions are particularly vulnerable to global hypoperfusion events; the parieto-occipital cortex is most susceptible. Parasagittal cerebral injury is most commonly seen in the full-term infant. Although most of these lesions are ischemic, approximately 25% are associated with hemorrhagic events in the perinatal period.    

Focal and multifocal ischemic brain necrosis

These lesions vary in terms of distribution and can be limited to a region supplied by an occluded artery or can be diffuse in cases of global hypoperfusion. Ulegyria may result, with preserved gyral crests adjacent to sulci marked by dyslamination, neuronal loss, and disorganized white myelinated fibers (see Media files 7-8).    

Periventricular leukomalacia (PVL)

This lesion, also called "white matter necrosis," is macroscopically characterized by the presence of discrete cavities or foci of parenchymal softening in the periventricular areas. In some cases, PVL can not be grossly appreciated. PVL is believed to be the result of compromised boundary zone perfusion between the ventriculofugal and ventriculopetal arteries. This area is particularly vulnerable secondary to the increased metabolic demands of white matter undergoing myelination. Microscopically, PVL manifests early as geographic coagulative necrosis. As the lesion evolves, reactive astrocytes, activated microglia, and macrophages become prominent in the lesional rim (see Media files 10-11).

• Search for CME/CE on This Topic »

• Hypoxic-Ischemic Brain Injury in the Newborn (Neurology)
• Neonatal Seizures (Neurology)
• Mental Retardation (Neurology)
• Follow-up of the NICU Patient (Pediatrics: Cardiac Disease and Critical Care Medicine)

• Gentamicin Clearance Not Impaired by Hypothermia

• Heatstroke During Endurance Exercise: Is There Evidence for Excessive Endothermy?
• A Comprehensive Review of Pediatric Endotracheal Suctioning: Effects, Indications, and Clinical Practice
• Cerebellar Hemorrhage in Extremely Low Birth Weight Infants: Incidence, Risk Factors, and Impact on Long-Term Outcomes